We are studying the cellular and molecular basis of autoimmune diseases with two purposes. First, we want to establish the pathogenic role and antigen-specificity of T cells that cause autoimmune diseases such as multiple sclerosis, clotting factor inhibition, insulin-dependent diabetes, among others. Second, we would like to determine the feasibility of specific antigen-induced apoptosis as a means of treating such autoimmune diseases. To these ends, we have made progress in the following areas: 1) we have reinitiated studies of recombinant molecules containing antigens potentially involved in multiple sclerosis with the goal of establishing a Cooperative RFesearch and Development Agreement to test such a form of therapy in a clinical trial. At present there is increasing evidence that myelin proteins antigens are the target of the autoimmune attack. By programmed the T cells that recognize such antigens to die, the effect of eliminating these cells on the disease can be demonstrated. 2) we are studying new highly sensitive diagnostic tests to detect end organ damage during autoimmune diseases to determine if these can provide an "early warning system" of autimmune attack; and 3) we are initiating studies of antigen-specific therapy to prevent the formation of blocking antibodies following factor VIII administration to hemophiliacs. We will also be initiating studies of a new transgenic mouse model for autoimmune thyroiditis. As part of these studies we are trying to understand the regulation of antigen-induced death by T cell receptor stimulation. By combining a highly sensitive "early warning system" to identify individuals with early immune-mediated organ damage with antigen-specific deletion approaches, we hope to provide effectively targeted therapy before there is extensive end-organ damage. These studies should yield important new insights into the pathogenesis and treatment of autoimmune diseases which is a widespread health problem in the U.S. particularly among working women.